Urethanes containing the lysergic



Patented Dec. 12, 1950 UNITED stares PATENT oFFicE.

URETHANES CONTAINING THE LYSERGIC ACI'D RING SYSTEM AND A PROCESS OFMAKING SAME" ited, Basel, Switzerland No Drawing. Application December16, 1947, Se-

rial No. 792,095. In Switzerland December 18,

and; obtainable by removalof the carboxyl group,

l3. denotes; alkyl, can. be prepared by converting lysergic acid orisolysergic acid azidesinto the corresponding. isocyanates and treatingthe same with an alcohol.

The asides. t lysergic acid orv isolysergic acid used as.- startingvmaterials. can, be prepared by known-processes. (see. A. Stoll and A.Hofmann, Helvetica Chimica Acta 26, 922, 944'. (1943);; U. S. Patent No.2,090,429),

The desired esters of carbamic acid can be. obtained in .ve y goodyields, if the azides are first converted into the isocyanates byheating the former in a suitable solvent, e. g. benzene, and adding-to.the boiling: solution the corresponding alcohol also present in a stateof ebullition. It isalso possible. to prepare the same urethanes by,

adding the crystallised azide of lysergic acid; or

isolysergic acid to the boiling alcohol. The isocyanate formed in thehot solventreacts imme: diately with the alcohol to form the urethane.In order to obtain good yields it is important that the solvent usediscompletely free from water.

It, is known that in the reactions of lysergic,

acid or isolysergic acid there is formed an equilibrium mixture of theisomeric forms (see A. Stoll and A. Hofmann, Helvetica Chimica Acta 25,953 (1943) Likewise there is obtained a, mixture of the two. isomericurethanes both when.

starting from lysergic acid or isolysergic acid,

whereby in the v first case G-methyl-ergolenyl-B and,' in the case ofisolysergic acid, fi-methyl-isoergolenyl 8-eurethane will predominate.

The. separation of the two isomers may be effeeted according toconventional methods, e. g. bra fract o a crystallisat on. of th a .v oo uitab e: sa ts. or .by m ans o th hr mat graphic adsorption analysis.

The new. urethanes are. relatively stable and formmostly wellcrystallising compounds which form Well crystallised salts which aremore or less soluble in water ccording. to. the nature of the acidradical. They show the Kellers colour reaction (with glacial acetic acidcontaining fer,- ric chloride and concentrated sulfuric acid). whichischaracter s i t r e natu a e g lka o d Arthur Stoll, Albert Hofmann,and Franz Troxler, Basel; Switzerland, assignors to Sandoz Linn.

They also show the blue fluoresence in ultra-violet light, which factalso is typical for the ergot allga; loids.

It, has, furthermore been found that in mammalians, the new derivativesexert a manifest, central stimulating action. For instance,v therespiratory function is strengthened, this stimulating action persistingfor a. relatively long time. and exceeding that of "Lobeline or otheranaleptics in duration,

. The. following examples, without being lirnlta tive, illustratethepresent invention.

Example-1 Preparation of (6-methyl-ergolenyl-8)-oarbamic acid methylester.

1.14 parts by weight of d-lysergic acid hydra;

1 zide are dissolved in 40 parts by volume of QQl-n hydrochloric acid,40 parts by volume of- Q.1-n sodium nitrite are added and then 45 partsby volume of 0.1-n hydrochloric acid dropwise added at 0 C.Crystallisation of the hydrochlorideof lysergic acid azide beginstowards the end of the zene solution is well. dried with sodium sulfateand is rapidly. heated to boiling and. thereupon boiled for 5 minutes.boiling methanol are added in one lot to. the

boiling solution, and the whole is boiled for: 5.- minutes to completethe formation. of the ure-v thane. After evaporating to dryness in a.vac-. uum 0.9 part by weight of crystallized crude product is. obtainedas residue.

For purification the urethane. is alternately re.- crystallized fromethanol and. chloroform. 0.55 part by weight of pure. (fi-methyl-ergolenyl-Bicarbarnic acid-methyl ester is obtained. Meltingpoint 236237 C. (decomp).

The. compound dissolves in parts of boiling chloroform from "whichsolution it crystallizes out on cooling in the form of 5-corneredleaflets. From 110 parts of benzene irregular 5 to 6 -cornered leafletsare obtained and from methanol or ethanol inswhich the product iseasilysoluble longish it-cornered plates containing solvent ofcrystallisation are obtained.

Analytical values: C1'7H19O2N3I Calculated: C 68.65 H644. N. 14,1 4Found: 0 68.48 H 6.25 N 14.45 68.79 6 .29 14.49

Kellers colour reaction-z like lysergic. acid,

parts by volume of Example 2 Preparation of (6 methyl isoergolenyl 8)carbamic acid methylester.

1.0 part by weight of the hydrazide of d-isolysergic acid is dissolvedin 35.5 parts by volume of 0.1-n hydrochloric acid, 3.55 parts by volumeof normal sodium nitrite added and 40 parts by volume of 0.1-n normalhydrochloric acid dropwise added at C. After 3 minutes 10 parts byvolume of n-sodium bicarbonate are added and the acid azide taken up in300 parts by volume of benzene. dried with sodium sulfate and heatedrapidly to boiling and boiled for 5 minutes. To the solution cooled to65 0. there is added in one lot 100 parts by volume of boiling methanoland the solution boiled for a further 3 minutes. It is then evaporatedto dryness in a vacuum and the crude product amounting to 0.92 part byweight recrystallized several times from methanol in which it is verysoluble in the hot, but only sparingly soluble in the cold and fromwhich long needles united into bundles and containing solvent ofcrystallisation are obtained. The (6- methyl-isoergolenyl-B)-carbamicacid methylester dissolves in 30 parts of benzene, 10 parts ofchloroform or parts of alcohol at the boiling point of the solvent. Fromthe last named solvent there crystallize polyhedra being free fromsolvent of crystallisation. M. P. 180 C. (decomposition) raj =+s4e(pyridine); +343 (chloroform) Analytical values: Cnl-hsOzNs:

Calculated: c 68.65 H 6.44 N 14.14 Found: 68.81 6.14 14.59

Kellers colour reaction: like lysergic acid.

Example 3 Preparation of (6 methyl-ergolenyl 8) carbamic acid ethylester.

1.08 parts by weight of d-lysergic acidhydrazide are converted into theazide as described in Example 1, and the same i taken up in 300 parts byvolume of benzene. The solution of benzene dried with sodium sulfate isquickly heated to boiling and boiled for 5 minutes. 100 parts by volumeof boiling ethyl alcohol are added to the boiling solution and the wholeboiled for a further 3 minutes and the solution evaporated to dryness ina vacuum.

The dried residue is subjected to chromatographic adsorption analysis on50 parts by weight of aluminium oxide. The substance is brought onto thecolumn in chloroform and this is developed with benzene. 0.861 part byweight of colorless urethane is obtained by elution in a single zonehaving a blue fluorescence in ultraviolet light. By recrystallizationfrom benzene there is obtained from it 0.620 part by weight of 6 to8-cornered leaflets of M. P. 237-238" C. (decomp).

[a] =+48 (pyridine); +51 (chloroform) The (6 methyl ergolenyl 8)carbamic acid ethyl ester dissolves at boiling temperature in 100 partsof benzene or parts of alcohol.

Analytical values: C18H21O2N32 Calculated: C 69.41 H 6.80 N 13.50 Found:69.45 7.21 13.62

Kellers colour reaction: like lysergic acid.

The benzene solution is.

4 Example 4 Preparation of (6-methyl-isoergolenyl-8) carbamic acidethylester.

0.? part by weight of d-isolysergic acid hydrazide is dissolved in 25parts by volume of 0.1-n hydrochloric acid, 5 parts by volume of 0.5-nsodium nitrite are added and 28 parts by volume of 0.1-n hydrochloricacid dropwise added at 0 C. After 5 minutes, 10 parts by volume ofn-sodium bicarbonate are added and the acid azide taken up in 500 partsby volume of ether. The ethereal solution is dried with sodium sulfateand carefully evaporated to dryness. The acid azide thus separates forthe greater part in the crystallized form.

The powdered azide is added in small portions to 100 parts by volume ofboiling alcohol in which it dissolves'spontaneously with foaming. Afterthe addition is completed it is boiled for another 3 minutes and thenevaporated to dryness. The dry residue is subjected to chromatographicadsorption analysis on 100 parts by weight of aluminium oxide. Thesubstance is brought onto the column in benzene solution, and this isdeveloped with the same solvent. By means of benzene 0.32 part by'weight of(6- methyl-isoergolenyl-8) -carbamic acid ethyl ester isobtained in a single zone giving a blue fluorescence in ultra-violetlight. This is obtained'by recrystallization from benzene in the form oflong needle-shaped prisms of M. P. 177 C.

[G]D2=+326 (pyridine); +33? (chloroform) The (6 methyl isoergolenyl 8)carbamic acid ethyl ester dissolves in 15 parts of benzene or less than20 parts alcohol at the boiling of these solvents.

Analytical values: ciaHz OzNaz Calculated: C 69.41' H 6.80 N 13.50Found: 69.39 7.16 13.77

Kellers colour reaction: like isolysergic acid.

From the aluminium oxide column there is finally obtained by means ofbenzene containing 2 per cent of alcohol further 0.15 part by weight of'the (6-methyl-ergolenyl-8)-carbamic acid ethyl ester described inExample 3.

Example 5 Preparation of (6-methyl-ergolenyl-8) and (6- methylisoergolenyl-8) -carbamic acid propyl esters.

1.136 parts by weight of d-lysergic acid hydrazide are converted intothe acid azide as'described in Example 1. This is taken up in 400 partsby volume of benzene. -The benzene solution, after thorough drying withsodium sulfate;

is rapidly heated to boiling and boiled for 5 minutes. To the boilingsolution there is added in one portion 100 parts by volume of boilingpropyl alcohol and the solution boiled for further}. 3 minutes. It isthen evaporated to dryness and the dry residue subjected tochromatographic adsorption analysis on 100 parts by weight of 7aluminium oxide.

By means of chloroform there is firsteluted 0.1 part by weight of an oilwhich does not crystallize from any solvent, the optical rotation of'which a] lies between +290 and +300. It'

consists of (6-methyl-isoergolenyl-8)-carbamic acid propyl ester. ,p

By means of chloroform to which A per cent of alcohol is added a secondzone is eluted which point.

l '=+47 (pyridine); +49.5 (chloroform) It dissolves in 50-60 parts ofboiling benzene or in 10 parts of boiling alcohol.

Analytical values: C19H23O2N3:

Calc.: C 70.11 H 7.13 N 12.92 Found: 70.48 7.26 13.33

Kellers colour reaction: like lysergic acid.

Example 6 Preparation of (6-methyl-ergoleny1-8)- and(6-methyl-isoergolenyl-8)-carbamic acid butyl esters.

1.136 parts by weight d-isolysergic acid hydrazide are converted intothe acid azide as described in Example 2, and this is taken up in 400parts by volume of toluene. The toluene solution after thorough dryingwith sodium sulfate is rapidly heated to boiling and boiled for minutes.100 parts by volume of boiling butyl alcohol are added in one lot to theboiling toluene solution and the solution boiled for a further 3minutes. It is then evaporated to dryness and the dry residue subjectedto chromatographic adsorption analysis on 50 parts by weight ofaluminium oxide.

By means of chloroform 0.59 part by weight of a non-crysallising oil isfirst eluted, the rotation of which lies between +260 and +280 and whichconsists of (6-methyl-isoergolenyl-8)- carbamic acid butyl ester.

By means of the same solvent a second uniform zone is then washed outwhich gives 0.27 part by weight of (6-methyl-ergolenyl-8-)-carbamic acidbutyl ester, which crystallizes from benzene in small 5-corneredleaflets or from alcohol in large B-cornered plates which melt at207-208" C. (decomp.).

[a] =+42 (pyridine); +49.5 (chloroform) The compound dissolves in 50parts of benzene and in parts alcohol, 10 parts acetone or 20 partschloroform at the boiling point of the solvents.

Analytical values: C20H25O2N32 Calm: C 70.75 H 7.43 N 12.39 Found: 70.857.35 12.92 70.94 7.40 12.81

Kellers colour reaction: as lysergic acid.

What we claim is:

1. The optically active urethanes of the for mula R.NHCOOR, wherein Rdenotes a radical selected from the group consis ing ofG-methylergolenyl-8-, of 6-methyl-isoergo1enyl-8- and of a mixture of6-methyl-ergolenyl-8- and S-methyl-isoergolenyl-8- and R denotes analkyl group containing 1 to 4 carbon atoms, which urethanes give theKellers color reaction and which are therapeutically useful compounds.

2. The (6-methyl-ergolenyl-8)carbamic acid ethylester of the formulawhich is a colorless crystalline compound melting with decomposition at237-238 C., having an optical rotation of [a] =+48 (pyridine) and,

6 +51 (chloroform) and giving the Kellers color reaction.

3. The (6 methyl isoergolenyl-8)-carbamic acid ethylester of the formulawhich is a colorless crystalline compound melting at 177 C., having anoptical rotation of [a] =+326 (pyridine) and +333 (chloroform) andgiving the Kellers color reaction.

4. The 6 methyl isoergoleny1-8)-carbamic acid propyl ester of theformula which is a non-crystallizing oil possessing the optical rotationof [al =+290-300 and giving the Kellers color reaction.

5. A process for the preparation of a urethane containing the lysergicacid ring system and corresponding to the formula R.NII.COO.R', whereinR denotes a member selected from the group consisting of the(i-methyl-ergolenyl-S- and 6- methyl-isoergolenyl-8-radicals, and Rdenotes an alkyl group with 1 to 4 carbon atoms, which comprises boilingan azide selected from the group consisting of lysergic acid azide,isolysergic acid azide and a mixture of lysergic and isolysergic acidazides in an anhydrous non-alcoholic solvent with a boiling lowmolecular alcohol containing 1 to 4 carbon atoms.

6. A process for the preparation of (ti-methylergo1eny1-8)-carbamic acidethyl ester, comprising the steps of heaing d-lysergic acid azide toboiling temperature in benzene solution, adding thereto ethyl alcoholand heating to boiling temperature until the intermediately formedisocyanate has been transformed into urethane.

7. A process for the preparation of (6-methylisoergolenyl-8)-carbamicacid ethyl ester, comprising the steps of' heating d-isolysergic acidazide to boiling temperatur in benzene solution, adding thereto ethylalcohol and heating to boiling temperature until the intermediatelyformed isocyanate has been transformed into urethane.

8. A process for the preparation of (fi-methylisoergo1enyl-8)-carbamicacid propyl ester, comprising the steps of heating d-lysergic acid azideto boiling temperature in benzene solution, adding thereto propylalcohol and heating to boiling temperature until the intermediatelyformed isocyanate has been transformed into urethane, and separating theformed iso-derivative from its isomer by chromatographic adsorption onaluminum oxide followed by elution with a solvent.

ARTHUR STOLL. ALBERT HOFMANN. FRANZ TROXLER.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,090,430 Stoll et a1. Aug. 17,1937 2,265,217 Stoll et al Dec. 9, 1941 OTHER REFERENCES Sidgwick:Organic Chemistry of Nitrogen (Oxford University Press, 1937), pp.374-376.

Troxler: Helv. Chim. Acta., Vol. 30, pp- 163- 167 (Feb, 1947).

1. THE OPTICALLY ACTIVE URETHANES OF THE FORMULA R.NHCOOR'', WHEREIN RDENOTES A RADICAL SELECTED FROM THE GROUP CONSISTING OF6-METHYLERGOLENYL-8-, OF 6-METHYL-ISOERGOLENYL-8- AND OF A MIXTURE OF6-METHYL-ERGOLENYL-8- AND 6-METHYL-ISOERGOLENYL-8- AND R'' DENOTES ANDALKYL GROUP CONTAINING 1 TO 4 CARBON ATOMS, WHICH URETHANES GIVE THEKELLER''S COLOR REACTION AND WHICH ARE THERAPEUTICALLY USEFUL COMPOUNDS.5. A PROCESS FOR THE PREPARATION OF A URETHANE CONTAINING THE LYSERGICACID RING SYSTEM AND CORRESPONDING TO THE FORMULA R.NH.COOR.R'' WHEREINR DENOTES A MEMBER SELECTED FROM THE GROUP CONSISTING OF THE6-METHYL-ERGOLENYL-8- AND 6METHYL-ISOERGOLENYL-8-RADICALS, AND R''DENOTES AN ALKYL GROUP WITH 1 TO CARBON ATOMS, WHICH COMPRISES BOILINGAN AZIDE SELECTED FROM THE GROUP CONSISTING OF LYSERGIC ACID AZIDE,ISOLYSERGIC ACID AZIDE AND A MIXTURE OF LYSERGIC AND ISOLYSERGIC ACIDAZIDES IN AN ANHYDROUS NON-ALCOHOLIC SOLVENT WITH A BOILING LOWMOLECULAR ALCOHOL CONTAINING 1 TO 4 CARBON ATOMS.